The management of elderly patients with acute myeloid leukemia (AML) and a poor performance status is challenging. An 89-year-old man with AML secondary to myelodysplastic syndrome (MDS) and a poor performance status (4) underwent treatment with methylprednisolone (mPSL) (125 mg/body), which resulted in a remarkable reduction of blast cells in the peripheral blood. Neutrophil counts were maintained or increased. Although the suppression was of short duration, mPSL was useful for disease control because it selectively reduced blast counts while maintaining the patient’s performance status. In vivo and in vitro findings suggested that mPSL had direct inhibitory actions on the survival of blast cells. On the basis of this experience, we gave the same mPSL dose to other elderly patients with MDS/AML (n = 5) or AML-M4 (n = 1) who had a poor performance status (3 or higher) and appeared unable to tolerate standard cytotoxic chemotherapies. Selective and significant blast cell reduction was observed in 4 of the 5 patients with MDS/AML, whereas no effects were seen in the AML patient. Although our experience is limited, these findings may provide a clue to understanding the mechanisms regulating the survival of blast cells of MDS/AML and indicate that mPSL may provide a benefit to a subset of these patients.